The Laboratory of Genetics and Physiology (LGP) explores how different cytokines control the development and physiology of distinct cell types through the Jak2/Stat5 generic signaling pathway. The tyrosine kinase Jak2 and the transcription factor Stat5 are present in virtually every cell type and they can be activated by a wide variety of cytokines. This signaling pathway is used by different cell types for distinct purposes. LGP scientists design experiments to understand molecular mechanisms underlying Jak2/Stat5 signaling in different settings. The goal is tom identify how different cell types exploited a generic signaling system for their own specific purposes. The systems under investigation include mammary tissue, hematopoietic lineages, liver, fat, skin and the pancreas. LGP uses mouse genetics to dissect general and cell specific functions. Since loss of the Stat5 locus results in perinatal lethality (Cui, 2004), LGP scientists have generated a mouse in which the entire 110 kbp Stat5 locus (containing the Stat5a and Stat5b genes) is bracketed by loxP sites (Cui, 2004). This mouse will serve as the foundation for future studies aimed to understand cytokine signaling in multiple cell types. The Jak2/Stat5 signaling pathways does not function in a vacuum but communicates with proteins, which is probably the basis of its specificity. Towards this end, LGP scientists and collaborators focused on the wnt signaling pathway and more recently on Notch signaling, which is essential for the biology of several stem cells, including the mammary gland. Research published in the current reporting period has established that Stat5 is essential for life. Conditional inactivation of Stat5 has provided information that in mammary epithelial tissue Stat5 is required for several distinct functions, including cell proliferation, differentiation and survival. LGP scientists have also shown that the gene encoding the gap junction protein connexin 26 is a genuine target of the transcription factor Stat5. Inactivation of the connexin 26 gene in mammary epithelium established the in vivo relevance of this observation. Similarly, it was shown that a-catenin is required for functional mammary development. LGP scientists have conintued to collaborate with other groups to inactivate genes in mammary epithelium and other cell types in mice using Cre-mediated recombination.